NATAP/CROI: Tenofovir Rectal Gel Acceptability/Safety

[Guest guest]

Subject: NATAP/CROI: Tenofovir Rectal Gel Acceptability/Safety

Rectal

Tenofovir Gel Clears Hurdle of Safety and Acceptability Study

19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012,

Seattle

Mark Mascolini

A 1% tenofovir gel proved safe and tolerable when applied rectally in MTN-007,

a phase 1 placebo-controlled trial that enrolled 65 sexually active men and women

[1]. Two placebo-controlled trials, CAPRISA 004 [2] and VOICE [3], tested

vaginally applied 1% tenofovir gel, with the smaller CAPRISA study finding a

39% reduction in HIV acquisition among women who used tenofovir rather than

placebo before and after sex. But the larger VOICE trial ended its vaginal gel

arm early when it became clear that daily tenofovir would not protect women

from HIV.

Many sexually active gay and bisexual men engage in anal intercourse, so knowing

whether a rectal microbicide is acceptable and safe for them is an important

prelude to efficacy trials. At the same time, research indicates that up to 35%

of sexually active women have had anal sex at least once,[4] so women may also

profit from a safe and effective rectal microbicide. Sexually transmitted

disease experts estimate that the risk of picking up HIV during unprotected anal

sex is at least 20 times higher than the risk with unprotected vaginal sex,

partly because the rectal lining is only 1 cell thick, compared with the

40-cell vaginal lining buffer [4].

In one earlier trial of rectally applied 1% tenofovir gel, RMP-02/MTN-006,

participants complained of diarrhea more than women using the vaginal 1%

tenofovir microbicide [4]. In an attempt to overcome this possible side effect,

researchers lowered the amount of glycerin in the gel, but they maintained the

1% concentration of tenofovir.

MTN-007 enrolled 45 men and 20 women at three US sites: Birmingham, Boston, and

Pittsburgh. No one had HIV infection, and everyone had receptive anal

intercourse at least once in the past year. They all agreed to abstain from sex

during the 4 to 8 weeks they would be in the study. Researchers randomized them

to 1% tenofovir gel (n = 16), to nonoxynol-9 (n = 16), to a placebo gel (n =

17), or to no gel (n = 16). Gel users in the trial had a series of tests

immediately before and after a single rectal application of the gel. A week

later, they applied the gel once daily for 7 straight days and then repeated

the series of tests.

Adherence to the assigned gel stood at or above 94% during the brief trial. The

investigators recorded mild (grade 1) adverse events in 46% of study

participants and moderate (grade 2) events in 28% of participants. Grade 1 and

2 adverse event rates were equivalent in the tenofovir group and the

placebo-gel group, both of which had lower rates than the nonoxynol-9 group. Two

grade 3 adverse events occurred, both in the no-gel control arm. A single grade

4 event affected 1 person in the placebo-gel group.

Epithelial sloughing (loss of rectal epithelial cells) did not change during

the trial. Neither did levels of fecal calprotectin, a major protein found in

inflammatory cells and a signal of inflammatory bowel disease [5]. Changes in

mucosal expression of chemokines and cytokines, T-cell phenotype, and rectal

microflora occurred mainly in the nonoxynol-9 arm. Vaginal irritation and

bleeding were common in people using nonoxynol-9 in an earlier trial that found

this spermicide may have facilitated HIV acquisition [4].

Acceptability rates among study participants were similar for tenofovir gel

(86.7%) and the placebo gel (93.3%), and much lower for nonoxynol-9 (62.5%).

The MTN-007 investigators concluded that the reduced-glycerin formulation of 1%

tenofovir gel "was safe and well tolerated and should be advanced to phase

2 rectal microbicide development." The phase 2 MTN-017 trial will assess

reduced-glycerin 1% tenofovir gel used rectally for up to 8 weeks in 186 people

in the United States, Thailand, Peru, and South Africa.

References

1. McGowan I Hoesley C, P, et al. MTN-007: a phase 1 randomized,

double-blind, placebo-controlled rectal safety and acceptability study of

tenofovir 1% gel. 19th Conference on Retroviruses and Opportunistic Infections.

March 5-8, 2012. Seattle. Abstract 34LB.

2. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al; CAPRISA 004 Trial Group.

Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for

the prevention of HIV infection in women. Science. 2010;329:1168-1174. Erratum

in Science. 2011 Jul 29;333:524.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001187/?tool=pubmed.

3. Microbicide Trials Network. MTN statement on decision to discontinue use of

tenofovir gel in VOICE, a major HIV prevention study in women. November 25,

2011. http://www.mtnstopshiv.org/node/3909.

4. Microbicide Trials Network. Questions and answers. MTN-007:

phase I tenofovir gel rectal safety study. http://www.mtnstopshiv.org/news/studies/mtn007/qa.

5. Lowry F. Fecal calprotectin a sign of inflammatory bowel disease. Medscape

Medical News. July 22, 2010. http://www.medscape.com/viewarticle/725672.